MANUSCRIPT CITATION

Relangi, D., et al. (2021). “Changes in PDA Treatment Strategy and Respiratory Outcomes in Premature Infants.” The Journal of Pediatrics. PMID: 33894266

REVIEWED BY

Sharada H. Gowda, MD, FAAP,
Asst Professor of Pediatrics
Baylor College of Medicine

Monika S. Patil, MD, FAAP
Asst Professor of Pediatrics
Baylor College of Medicine

TYPE OF INVESTIGATION

Clinical prediction guides

QUESTION

Do premature infants (P) benefit from closure of Patent Ductus arteriosus (PDA) (I) compared to those who are managed conservatively (C) in preventing bronchopulmonary dysplasia (BPD) (O) earlier in the postnatal period (T)?

METHODS

• Design: Prospective observational comparative study of two epochs with data collected retrospectively.
• Allocation: Not applicable
• Blinding: Not applicable
• Follow-up period: 2 years for epoch 1 and 4 years for epoch 2
• Setting: Level IV referral NICU
• Patients: Infants 23-30 weeks gestational age (GA) at birth were compared with infants of similar gestational age and demographical data between two epochs, Epoch 1 and 2. The study ranged from a period of January 1, 2005 to December 31, 2007 (Epoch 1), and the period of January 1, 2011 to December 31, 2015 (Epoch 2). The authors included patients with echocardiographic evidence of PDA and stratified into mild, moderate and severe based on size, shunt level and gestational age at the first echo. Additionally, timing of initial PDA treatment, type of treatment administered, and incidence of PDA ligation were collected. Demographic data included GA (determined by the best obstetric estimate using the last menstrual period or early ultrasound examination), birth weight (BW), small for gestational age (SGA, defined as BW < 10th centile for GA), race, sex, multiple pregnancy, preeclampsia, chorioamnionitis, antenatal steroid administration and Apgar score at 5 minutes. Early comorbidities of respiratory distress, culture proven sepsis and postnatal steroid use. Authors used the NICHD NRN BPD consensus definition for infants with GA <32 weeks to categorize and classify their patient population, i.e., treatment with oxygen for at least 28 days with categorization into the following three subgroups at 36 weeks’ postmenstrual age (PMA): (1) mild (breathing room air); (2) moderate (need for a <0.3 fraction of inspired oxygen (FiO₂), and (3) severe (need for ≥0.3 FiO₂ and/or positive pressure support). Infants with BPD who died of respiratory causes before the assessment date (i.e., after 28 DOL and before 36 weeks PMA) were included in the analysis and considered to have “severe disease.” The study also collected data on comorbidities such as Necrotizing enterocolitis (NEC): Bell’s stage 2 and above, and intraventricular hemorrhage (IVH) grade 3 and above.
• Intervention: Retrospective study using a prospectively collected data set to examine differences in patient outcomes during non-protocol based preferred clinical care of neonates in a level IV NICU
• Outcomes: Comparing the incidence of BPD in two epochs, one with >90% treatment for PDA and the second one with expectant management.
  • Primary outcome: BPD. Authors used the NICHD NRN BPD consensus definition for infants with GA <32 weeks to categorize and classify their patient population, i.e., treatment with oxygen for at least 28 days with categorization into the following three subgroups at 36 weeks’ postmenstrual age (PMA): (1) mild (breathing room air); (2) moderate (need for a <0.3 fraction of inspired oxygen (FiO2), and (3) severe (need for ≥0.3 FiO2 and/or positive pressure support).
  • Secondary outcomes: Composite outcomes of death or severe BPD
• Analysis and Sample Size: Of 1253 patient charts reviewed, 710 met the inclusive criteria. While the remaining patients were excluded, no specifics are given for those exclusions. In Epoch 1, 309 patients met the included in the cohort and in Epoch 2 there were 401 patients.
• Patient follow-up: Not applicable

MAIN RESULTS

This prospective observational study included a total of 710 infants <30 weeks’ gestation. About 59% in epoch 1 and 54% in epoch 2 had BPD. Authors conclude that a stringent therapeutic intervention of PDA mitigates the risk of death or severe BPD. When utilizing a univariate analysis, authors found no significant association of severe BPD or death between two epochs. When they did a multivariate analysis with multiple confounding factors (including sex, 5 minute Apgar score, severity of RDS and sepsis) they found an increase in BPD in the conservative management arm, or Epoch 2.

On multiple logistic regression, there was no increase association with NEC or IVH which is an important finding.

CONCLUSION

Authors conclude that compared to early aggressive intervention, there was an association with BPD and the combined outcome of death and BPD in patients with late conservative intervention. This difference was more apparent in infants in the 27-30 weeks gestation group compared with the 23-26 weeks gestation group.

COMMENTARY

Premature newborns with respiratory failure often require mechanical ventilation. Prolonged mechanical ventilation, lower gestational age, lower birthweight, small for gestational age, resuscitation, infections, hyperoxia, genetic factors, poor nutrition and male gender predispose these patients to bronchopulmonary dysplasia (BPD)[1]. Patent ductus arteriosus (PDA) contributes to respiratory failure through pulmonary overcirculation[2, 3]. Previous studies have shown an association between PDA and BPD but not causality. This uncertainty about the clinical impact of PDA has resulted in a variety of treatment approaches. Many centers have adopted protocols incorporating a combination of expert opinion guidelines and  echocardiography to diagnose and manage a hemodynamically significant (HDS) PDA[4, 5]. However, these guidelines and interpretations may not be followed due to bedside clinician’s discretion and lack of equipoise.

This study includes over 400 patients that were 23-26 weeks gestation, which are the patients most likely to have PDA and BPD. It adds insight into outcomes of the extremely low birth weight (ELBW) in the recent era of improved modern neonatology practices which include gentle ventilation, early extubation, careful fluid management, and aggressive nutritional support.

Authors concluded that delayed closure of PDA was associated with development of BPD at their center, but do not delineate outcomes based on size of PDA, or specify whether the treatment options were based on institutional protocols or clinical guidelines, nor do they identify criteria for distinguishing HDS PDA.  Additionally, the incidence of atrial septal defect (ASD), an intracardiac lesion causing increased pulmonary blood flow, was not addressed in both epochs. Existing literature describes an association between ASD and BPD secondary to pulmonary vascular remodeling, similar to PDA[6].

Limitations of this prospective observational review include the inability to account for multiple confounding variables reported in the literature including differences in oxygen saturation limits. Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders[7, 8]. Other important factors impacting the development of BPD such as fluid management and nutritional status were also not addressed in this study. Moreover, this study did not mention if there was a difference in adminstratation between the epochs for two medications which are known to reduce the incidence of BPD: vitamin A and caffeine. Mechanical ventilation vs. noninvasive ventilation, and duration and type of postnatal steroid used were also not described. Finally, data from this study is also less applicable because recent evidence on transcatheter PDA closure in extremely premature patients shows promise and may also impact BPD outcomes[9].

The question is whether eliminating the pulmonary overcirculation from PDA will help reduce the risk of BPD in the current era of NICU care. This study makes it difficult to know if it was actually the treatment of the PDA that made the difference, or improved care trajectory of premature infants. Since therapeutic interventions are not benign, clinicians must carefully weigh risks and benefits of any therapy. To achieve that, we need a large RCT of catheter device closure vs medication in extremely premature patients which proves superiority over expectant management.

REFERENCES

1. Chess, P.R., et al., Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol, 2006. 30(4):p. 171-8.
2. Benitz, W.E., Patent Ductus Arteriosus in Preterm Infants. Pediatrics, 2016. 137(1).
3. Mailaparambil, B., et al., Genetic and epidemiological risk factors in the development of bronchopulmonary dysplasia. Dis Markers, 2010. 29(1): p. 1-9.
4. Philip, R., et al., Hemodynamic and clinical consequences of early versus delayed closure of patent ductus arteriosus in extremely low birth weight infants. J Perinatol, 2021. 41(1): p. 100-108.
5. Ibrahim, T., et al., Selective Treatment of PDA in High-Risk VLBW Infants With Birth Weight ≤800 g or <27 Weeks and Short-Term Outcome: A Cohort Study. Front Pediatr, 2020. 8: p. 607772.
6. Kumar, K.R., et al., Association of Atrial Septal Defects and Bronchopulmonary Dysplasia in Premature Infants. J Pediatr, 2018. 202: p. 56-62.e2.
7. Lingappan, K., et al., Sex-specific differences in neonatal hyperoxic lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2016. 311(2): p. L481-L493.
8. Fulton, C.T., et al., Gene Expression Signatures Point to a Male Sex-Specific Lung Mesenchymal Cell PDGF Receptor Signaling Defect in Infants Developing Bronchopulmonary Dysplasia. Sci Rep, 2018. 8(1): p. 17070.
9. Sathanandam, S., et al., Initial clinical experience with the Medtronic Micro Vascular Plug™ in transcatheter occlusion of PDAs in extremely premature infants. Catheter Cardiovasc Interv, 2017. 89(6): p. 1051-1058.